The current available therapies for the treatment of pain utilize several classes of compounds like Non-steroidal anti-inflammatory drugs (NSAID's) and opioids. Most NSAIDs have one or more side effects such as irritation of the gastrointestinal (GI) tract leading to Nausea/Vomiting, Gastric ulceration/bleeding, Dyspepsia, inflammatory bowel disease, altered renal function, deleterious effects on the cardiovascular system and many more. Opioids result in emetic, constipatory and negative respiratory effects, as well as the potential for addiction. Hence, there is a great unmet need for drugs that alleviate pain without the adverse effects caused by the current pain therapies.
Trks and neurotrophins are well known for their effects on neuronal growth and survival through their regulation of cell proliferation, differentiation, apoptosis, and survival of neurons in both the central and peripheral nervous systems. Trk kinases, with three highly homologous isoforms, TrkA, TrkB, and TrkC are activated by high affinity growth factors named neurotrophins with Nerve growth factor (NGF), which activates TrkA; brain-derived neurotrophic factor (BDNF) and NT-4/5, which activate TrkB; and NT-3, which activates TrkC. The binding of neurotrophins to the extracellular domain of Trks causes the Trk kinase to autophosphorylate at several intracellular tyrosine sites and triggers downstream signal transduction pathways such as PI3K, Ras and PLC-γ pathways (Molecules 2015, 20(6), 10657-10688).
NGF signaling via TrkA is recognized to play an important role in pain sensation. Genetic studies in humans with TrkA loss of function mutations have provided evidence of the significant role of NGF signaling in pain sensation (ClinAuton Res 2002; 12 Suppl 1: 120-32). Currently, novel pain treatments are highly desired due to low efficacy and/or undesirable gastrointestinal, renal and psychotropic side effects of NSAIDS and opiates. NGF expression is increased in various pain conditions and administration of NGF increases pain sensitivity. Inhibition of NGF signaling via TrkA using a variety of antibody and small molecule based approaches have been shown to be effective in preclinical animal models for pain (Anesthesiology. 2011 July; 115(1):189-204). Selective TrkA inhibition demonstrated equivalent efficacy to nonselective Trk inhibitors. Intermittent TrkA inhibition using a small molecule results in comparable efficacy to NGF antibodies in pain models (Andrews IASP, 2012). NGF mab, Tanezumab demonstrated excellent clinical efficacy in Osteoarthritis, chronic low back pain and diabetic peripheral neuropathy. TrkA selective small molecule inhibitors have therapeutic utility for various pain conditions. Efficacy of Anti-TrkA antibodies and anti-NGF antibodies for treatment of inflammatory and neuropathic pain have been demonstrated in vivo models in WO2006/131952 and WO2005/061540.
Trks play key role in malignant transformation, chemotaxis, metastasis, and survival signaling in human tumors (Cancer Lett 2001; 169:107-14). Oncogenic activation of TRKA occurs through genomic rearrangement and the creation of a gene fusion where extracellular domain of TrkA is replaced by fusion with another gene with the kinase domain intact results in constitutive activation of TrkA pathway. A number of NTRK1 gene fusions have been reported in a variety of cancers such as NSCLC, spitz melanoma, colorectal cancer, cholangiocarcinoma, soft tissue sarcoma, glioblastoma and papillary thyroid carcinoma (Cancer Discovery Jan. 1, 2015 5; 25) with more new fusions being reported based on the NGS sequencing of patient DNA. Trk inhibitors such as Entrectinib and LOXO-101 have demonstrated significant tumor regression in patients with Trk fusions (Cancer Discov. 2015 October; 5(10):1049-57, J Natl Cancer Inst. 2015 Nov. 12; 108(1)).
In addition to gene fusions, molecular alterations such as an in-frame deletion of NTRK1 (ΔTRKA) in acute myeloid leukemia (AML) and a splice variant of NTRK1 (TRKAIII) in neuroblastoma have been functionally characterized as oncogenic. Autocrine and paracrine signalling by Trk receptors have been implicated as protumorigenic in several different tumor types. An autocrine loop involving TrkA and NGF is associated with protumorigenic activity in both breast and prostate carcinomas (Mol Cell Biol. 2000 December; 20(23):8655-66, Clin Cancer Res 2001; 7:2237-45). Expression of TrkA and TrkC wild-type receptors is associated with a positive prognosis in patients with neuroblastoma (excluding expression of the splice variant TRKAIII) (N Engl J Med. 1993 Mar. 25; 328(12):847-54). Hence, TrkA inhibitors have potential for cancers driven by activated TrkA signaling due to molecular alterations or autocrine/paracrine signalling due to increased expression of TrkA and/or NGF.
TrkA is expressed in the bone forming area in mouse models of bone fracture (Bone. 2000 June; 26(6):625-33) and Trk inhibitors induce apoptosis of proliferating osteoblasts (Cancer Res. 2002 Feb. 15; 62(4):986-9) suggesting use of Trk inhibitors for bone remodelling diseases such as bone metastases in cancer patients.
NGF and TrkA are expressed in immune cells and a localized increase in NGF at the sites of inflammation is observed during the inflammatory process. Inflammatory cytokines such as IL-1beta, TNF-alpha and IL-6 are able to modify the basal production of NGF in the organism and induce the synthesis of NGF in a variety of cell types and tissues. TrkA-NGF pathway is also involved in a number of disorders such as Osteoarthritis, Multiple Sclerosis (J Clin Immunol. December 2011; 31(6): 1010-1020) and in inflammatory diseases including Asthma (Pharmacology & Therapeutics 2008, 117(1), 52-76), Interstitial Cystitis (The Journal of Urology 2005, 173(3), 1016-21), inflammatory bowel diseases including Ulcerative Colitis and Crohn's disease (Gut 2000, 46(5), 670-678), neurodegenerative diseases like Alzheimer's disease, Huntington's disease, Progressive Supranuclear Palsy (J Alzheimers Dis. 2014; 40(3): 605-617, ActaNeuropathol. 1998 November; 96(5):495-501) and Neurogenic Erectile Dysfunction (European Urology, November 2014). Inhibition of Trk pathway has been shown to be effective in preclinical models of inflammatory diseases. Therefore, TrkA kinase inhibition can be used as a new methodology for the treatment of these diseases.
Trk kinases are also involved in skin diseases like atopic dermatitis (Archives of Dermatological Research 2006, 298(1), 31-37), Eczema, Psoriasis (J. Investigative Dermatology 2004, 122(3), 812-819), Pruritis (Acta Derm Venereol 2015; 95: 542-548), restenosis and Atherosclerosis. TrkA inhibition is also implicated for the treatment of fibrotic disorders based on the ability of Connective Tissue Growth Factor (CTGF) to activate TrkA signaling (Fibrogenesis Tissue Repair. 2012 Jun. 6; 5(Suppl 1):S24). TrkA inhibitors may also be useful in treatment of endometriosis (Reprod Sci. 2011 December; 18(12):1202-10, Hum Reprod. 2009 April; 24(4):827-34), diabetic peripheral neuropathy (Brain Res. 2000 Jun. 9; 867(1-2):149-56, Diabet Med. 2009 December; 26(12):1228-34), chronic prostatitis/chronic pelvic pain syndrome (Urology. 2002 April; 59(4):603-8, BJU Int. 2011 July; 108(2):248-51) and Chagas' disease (Cell Host Microbe. 2007 Jun. 14; 1(4):251-61).
Several classes of small molecule inhibitors of Trk kinases are known to be useful for treating pain or cancer. International Publication No. WO2014/078378, WO2012/125668, Patent publication numbers US20150336970, AU2015200511 and Expert Opinion on Therapeutic Patents (2009) 19, 305-19 and Expert Opinion on Therapeutic Patents (2014), 24(7):731-744 discloses the classes of compounds that are said to be inhibitors of Trk kinases which could be useful for treating diseases such as pain, cancer, restenosis, Psoriasis, thrombosis, atherosclerosis, Inflammatory diseases, neurodegenerative diseases or the like.
Hence, pharmacological inhibition of TrkA pathway offers promising approaches for the treatment of a variety of diseases dependent on hyperactivation of TrkA pathway.